System and method for controlling vascular responses

ABSTRACT

A method and a system are disclosed for producing changes in systemic arterial blood pressure, cerebrospinal fluid pressure and heart rate; as well as producing selective brain hypothermia in animals by irrigating the nasal mucosa.

United States Patent [1 1 Magilton et a].

[ 1 Dec. 4, 1973 SYSTEM AND METHOD FOR CONTROLLING VASCULAR RESPONSES [75] Inventors: James II. Magilton; Curran S. Swift,

both of Ames, Iowa [73] Assignee: Iowa State University Research Foundation, Inc., Ames, Iowa 22 Filed: Aug. 13, 1971 21 App1.No.: 171,575

[52] US. Cl. 128/400, 128/401 [51] Int. Cl. A61f 7/00 [58] Field of Search 128/400, 303.1, 401,

[56] References Cited UNITED STATES PATENTS 3,074,410 1/ 1963 Foster 128/400 3,238,944 3/1966 Hirschhom 128/400 3,170,465 2/1965 Henney et a1 128/401 OTHER PUBLICATIONS .1. N. Hayward et a1.-Brain Research lo (1969), pp. 417-440 .1. 1-1. Magiiton et al.-Jouma1 of Applied Physi' o 1ogyVol. 27, No. 1, p. 18 J. H. Magilton et a.l.-The Physiologist, Vol. 10, No. 3 -Aug. 1967, p. 241

Primary Examiner--Lawrence W. Trapp Attorney-James J. Hill [57] ABSTRACT A method and a system are disclosed for producing changes in systemic arterial blood pressure, cerebrospinal fluid pressure and heart rate; as well as producing selective brain hypothermia in animals by irrigating the nasal mucosa.

5 Claims, 10 Drawing Figures PMENTEDUEB 41975 3,776,241

SHEET 10F '2 F HEART RATE 7 M Fig. 3B? Fi 3c;

QSF mssms W930i. E F f INVENTORS JAMES H. MAG/LTOIV CURRAN S. SWIFT WgM/QM SYSTEM AND METHOD FOR CONTROLLING VASCULAR RESPONSES BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method and system for producing: 1) cardio-vascular changes; and 2) selective brain hypothermia in a mammal in response to irrigating the nasal mucosa with water at variable temperature levels.

It has been suggested that the hazards of cardiovascular surgery and cerebral edema following brain trauma would be greatly reduced if. the temperature of the brain were reduced within controlled limits. Three reasons for this suggestion are that: (1) oxygen consumption in the brain decreases almost linearly with lowering of the temperature under controlled conditions; (2) cerebral blood flow and mean systemic arterial blood pressure decrease while cerebrovascular resistance increases with hypothermia; and (3) cerebral blood flow and brain volume change in the same direction. This hypothermia would reduce the blood flow to the brain, thereby reducing brain volume, and: increase the tolerance of the brain to hypoxia.

An early method of reducing the temperature of the brain included circulating a refrigerated solution through a metal capsule (with connecting tubing) which had been placed in the brain. Total body hypothermia, as an indirect means of cooling the brain, replaced this early method. Total body hypothermia has cetain disadvantages including the need for a large amount of equipment to maintain the low temperature, and the tendency of the heart to go into fibrillation at low body temperatures. Attempts have been made, therefore, to produce selective brain hypothermia-- that is, lowering of the brain temperature without lowering the temperature of the rest of the body significantly. One suggested method of selected brain hypothermia is to cool the esophagus, as reported in the technical documentary port No. SAM-TDE-63-l9 of the USAF SCHOOL OF AEROSPACE MEDICINE, Aerospace Medical Division, Brooks Air Force Base, Texas. Attempts have also been made to achieve selective brain hypothermia by cooling blood destined for the head in an extra-corporeal cooling system. The objections to this approach have caused it to be abandoned. At present there is no surgical technique to our knowledge that is commonly accepted for the selective inducement of brain hypothermia.

2. Published Work An abstract of a paper given by us was published in The Physiologist, Vol. 10, No. 3, August, 1967, in which we reported achieving cooling of the brain of the canine by irrigating the alar folds of the maxilloturbinates with water having a temperature of 12.0 C. We reported that the venous blood passing from the alar folds into the cavernous sinus cooled the arterial blood passing to the brain by way of the latter sinus. This arterial blood absorbed heat from the brain after passing through components of the circle of Willis and their distributing vessels. We postulated at the time of this work that two separate heat exchange mechanisms were involved one, which we called the external heat exchange system, is located in the alar fold of the maxilloturbinatc and cools blood which flows into the cavernous sinus by way of the angularis oculi vein, and the second, which we called the internal heat exchanger, is

in the cavernous sinus where heat is ltransferred from the warm arterial blood destined for the brain to the cooler venous blood inthe cavernous sinus.

In a subsequent article of Haywardand Baker entitled A Comparative Study of the Role of Cerebral Arterial Blood in the Regulation of Brain Temperature in Five Mammals," published in Brain Research, Vol. 16, p. 417, work was reported in this area on different species of mammals, and as a result,.the authors classified their subjects into two broad categories: (1) those of the intemal carotid artery type which includes the monkey and the rabbit and is characterized by having a single large vessel passing through the cavernous sinus thereby providing a flow pathway from the common carotid artery to the circle of Willis; and (2) the carotid rete type which is characterized by having more than one communicating vessel from the common carotid artery to the circle of Willis: 1) via the cavernous sinus as in the dog and sheep; and 2) in close proximity to a venous plexiform network in cats.

Based on their experiments, these researchers concluded that heat exchange occurs between the cooler venous blood in either the cavernous sinus (for the dog and sheep) or the venous plexiforrn network (in the case of the cat) and the warmer arterial blood only in those animals of the carotid rete type. Further, these researchers believed themselves to have demonstrated that for animals having a single internal carotid artery conducting blood through cavernous sinus, there was no heat exchange at the base of the brain. These studies concluded that this was a major difference between the two classifications.

The results of our further experimental work on the physiological heat exchange systems for controlling the brain temperature of a dog are reported in an article appearing in the IEEE Conference Record, Fifih Annual Rocky Mountain Bioengineering Symposium entitled Description of Two Physiological Heat Exchange Systerns for the Control of Brain Temperature and in an article published in. the Journal of Applied Physiology, Vol. 27, No. l, p. 18, entitled Response of Veins Draining the Nose to Alar-Fold Temperature Changes in the Dog.

SUMMARY As a result of our experimentation, including work performed on horses which have a single large carotid artery leading from the common carotid artery and passing through the cavernous sinus to the circle of Willis, we believe we have demonstrated that selective brain hypothermia can be induced by irrigating the nasal mucosa of animals with a single internal carotid artery as well as those with a carotid rete with cold water. As a result of further experimentation with dogs, we have been able to induce changes in cerebrospinal fluid pressure, systemic blood pressure, and heart rate by irrigating the nasal mucosa. That is, we have been able to selectively increase the cerebrospinal fluid pressure, systemic blood pressure and heart rate by irrigating the tip of the nose with hot water; and we have produced reductions in cerebrospinal fluid pressure, systemic blood pressure and heart rate by irrigating the tip of the nose with cold water. Thus, we believe we have demonstrated a method of controlling blood flow to the brain of a mammal. While not limiting the effect of our invention, we postulate that there are two principal physiological mechanisms or systems which have a bearing on the brains s temperature. One such system we call the venous temperature control system; and it regulates the cooling of the venous blood destined for the cavernous sinus. The second system we call the cardio-arterial control system; and it acts in a manner to assist the venous temperature control system in regulating brain temperature. That is, when the venous control system has reached the limits of its capability to cool the venous blood, the cardio-arterial system will further influence the rate of heat exchange occurring between arterial and venous blood in the cavernous sinus by apparently altering arterial blood flow through the sinus. We believe the arterial flow through the cavernous sinus will be altered as a result of the changes in heart rate, systemic arterial pressure and cerebrospinal fluid pressure which we have demonstrated in our work.

When the regulatory effects of both of these physiological systems are overridden by irrigating the nasal mucosa with a medium of adequate cold temperature one can induce selective brain hypothermia and hence alter the flow of cerebral arterial blood.

Although the invention is not so limited, some of the clinical applications, as alluded to above, include selectively reducing the temperature of the brain without causing corresponding low temperatures in the remainder of the body. This has an advantage in heart surgery due to the fact that the oxygen requirement of the brain is reduced linearly with reduction in brain temperature. Therefore longer interruptions in cerebral blood flow can be tolerated. In addition, the heart can be maintained at near normal body temperature which reduces the propensity of this organ to go into fibrillation when manipulated in surgery.

Other features and advantages of the present invention will be apparent to persons skilled in the art from the following detailed description of a preferred embodiment accompanied by the attached drawing wherein identical reference numerals will refer to like parts in the various views.

THE DRAWING FIG. 1 is a pictorial diagram of the head of a subject dog showing the irrigation of the nose and the placement of temperature sensors on the angularis oculi veins.

FIG. 2 is a graph illustrating changes in cerebrospinal fluid pressure and arterial blood pressure resulting from the irrigation;

FIGS. 3A-3G are graphs illustrating the various vascular responses during irrigation; and

FIG. 4 is a block schematic diagram of a system for use in the practice of the present invention.

DETAILED DESCRIPTION We have shown in our laboratory that temperature alone can produce changes in the cardio-arterial system of animals which appear to vary cerebral blood flow and cerebral temperature in a manner that has not been reported elsewhere. The cardio-arterial changes are seen as a change in systemic arterial blood pressure (ABP), cerebrospinal fluid pressure (CSFP) and heart rate (HR). These cardio-arterial changes were induced by changing the temperature of the venous blood destined for the cavernous sinus by irrigating the alar fold of the maxilloturbinate. These cardio-arterial changes were such as to indicate that an increase in cerebral blood flow occurred when the temperature of the nasal mucosa was increased by irrigation with warm water; and a decrease in cerebral blood flow was indicated when the nasal mucosa was irrigated with cold water. Further, these cardio-arterial changes appear to be brought about by an autonomic reflex uniquely responsive to temperature. That is, the usual response to autonomic manipulation is such as to maintain a constant cerebral blood flow; whereas the autonomic response to the temperature changes we employed appears to have altered cerebral blood flow (heat making the flow increase and cold making it decrease). Furthermore, these cardio-arterial changes have occurred independently of carbon dioxide, oxygen and pH levels of the arterial blood, as has already been reported.

We believe that brain temperature regulation is accomplished through the agency of two systems. The first system provides for irrigating or circulating the surface of the nasal mucosa (more specifically, the alar fold of the maxilloturbinate) with an external media such as water, air or other gas. A portion of this temperature conditioned blood flows to the cavernous sinus where it baths arteries which conduct blood to the brain. In our early work this system was referred to as the extemal heat exchange mechanism; in our present work it is referred to as the venous temperature control system (VTCS). The second system involves control of the blood flow in the arteries just mentioned which are being bathed in the venous blood in the cavernous sinus which, in turn, has been temperature conditioned at the site of the external heat exchange mechanism. In our early work this system was referred to as the internal heat exchange mechanism; in our pres ent work it is referred to as the cardio-arterial control system.

VENOUS TEMPERATURE CONTROL SYSTEM Intracerebral temperature gradients are basically dependent upon the rate of removal of heat from the brain by arterial blood. This arterial blood is cooled by the flow of heat from the arterial blood to venous blood in the cavernous sinus. The temperature of the venous blood, in turn, is regulated by what is referred to herein as the venous temperature control system (VTCS). This system functions in two ways. The first includes a transfer of heat from the vessels in the nasal mucosa (that is, the alar fold of the maxilloturbinate) to the irrigating water or circulating air or other gas. The second manner in which the venous temperature control system works is to regulate the differential blood flow from the vessels in the nasal mucosa via the dorsal nasal veins to the angularis oculi veins on the one hand, and the facial veins on the other hand. The blood entering the angularis oculi veins flows through the ophthalmic veins to the cavernous sinus where it baths arterial blood destined for the brain. The blood entering the facial veins bypasses the cavernous sinus.

We have established through experiments the existence of a feedback control pathway from the brain to the venous temperature control system. We selected man as the experimental subject in an attempt to demonstrate this feedback control. The reasons we selected man were: (1) the anatomical arrangement of the nec essary structures is similar to that in the dog; (2) the subjects would be fully cooperative and would be able to perform precise mental tasks; and (3) previous experimental work (5) has shown that mental activity increases metabolic rate which, in turn, increases heat production. As a result of our work, physiological evidence that the venous temperature control system is involved'in brain temperature regulation was shown. it was found that mental activity (subtracting from 5000 by sevens as fast and accurately as possible) was accompanied by adjustments in the venous temperature control system which resulted in changes in the temperature of the angularis oculi veins (the assumption is made that an increase in metabolism in an organ is accompanied by an increase in the temperature of the or gan).

Further evidence pointing to the involvement of the venous temperature control system in brain temperature regulation was seen in the unanesthetized sheep where an increase in the temperatureof the reticular formation was accompanied by a coolingof the nasal mucosa. In this case an increase in the temperature of the reticular formation .was shown to occur by direct measurment. The cooling of the nasal mucosa in synchrony with the temperature changes occurring in the brain demonstrates the adjusting of the venoustemperature control system to obtain optimum brain temperature.

There is also evidence that adjustments which occur in the venous temperature control systems do not depend upon conscious activity. For example, in dogs under sodium pentobarbital anesthesia, uniformity was found 'to be lacking in the shape of the temperature curves between the angularis oculi and facial veins on the homolateral side. These variations in temperatures indicate variations in blood flow in the respective veins, and it is therefore evident that the homolateral reflex pathways involving the venous temperature control system are functional under anesthesia. Additionally, not only are the reflex pathways between the veins on the homolateral side intact (angularis oculi and facial) but also, the reflex pathways between veins of the venous temperature control system on opposite sides are intact and functional (evidenced by,lack of uniformity between the temperatures of the right and left angularis oculi veins).

These variations in blood flow between the angulan's oculi and facial veins on the same side and between the angularis oculi veins on opposite sides is considered important because blood entering the angularis oculi vein enters the cavernous sinus by way of the ophthalmic vein, whereas blood entering the facial vein passes into the external maxillary and then into the external jugular vein, thus bypassing the cavernous sinus. It is evident then that the blood entering the angularis oculi vein is involved with heat transfer (consequently brain temperature regulation) between arterial blood destined for the brain and venous blood in the cavernous sinus, whereas the blood entering the facial vein is not.

We have found evidence that autonomic control exists at the level of the angularis oculi and facial veins not only in the time-response variation of these veins between coldand hot-water irrigation as will be discussed, but also in the response of the angularis oculi veins to the clamping of the facial veins.

The mode of action of the autonomic innervation to the vessels in the venous temperature control system is considered important because of the system's involvement with brain temperature regulation, as previously mentioned. In this regard, the nasal vessels possess unique neural characteristics which indicate that their response to the autonomic stimulation is different from the responses of vessels in other parts of the body of autonomic stimulation. For example, there is reason to believe that the frequency of sympathetic impulses necessary to maintain vascular tonus and to mediate reflex vasoconstriction is different in the nasal vessels than in vessels in other parts of the body. If this is the case, then the sympathetic nervous system could exert differential control over the nasal veins on the one hand and the dorsal nasal, angularis oculi, and facial veins on the other hand, by means of variation in the impulse frequency.

Another example of the uniqueness of neural characteristics of arteries and veins in the nasal passage is that adrenergic receptors cannot be physiologically demonstrated in them. This means that in situations of high emotional stress, accompanied by adrenergic dominance, the only response attainable is constriction of the arteries and veinsin the nasal passage. This agrees with work done by others wherein adrenalin was injected intravenously and produced a marked constriction of the vessels lining the nasal passage. This constriction results in less cooling of the venous blood in the venous temperature control system due to a reduction in the rate of heat transfer occurring from the vessels to the ambient air.

If the assumption can be made that emotional stress situations are often accompanied by an increase in heat production in the brain due to an increase in mental activity, then a situation could develop during emotional stress where an increase in brain temperature would be accompanied by a decrease in the efficiency of the cooling system for the brain.

As already mentioned, we believe that brain temperature regulation is accomplished by the interaction of two systems: (1) cooling of venous blood destined for the cavernous sinus (the venous temperature control system described previously) and (2) control of the cerebral blood flow through the cavernous sinus by a cardio-arterial control system. The more efficient the venous temperature control system is, the less the cardioarterial control system will have to alter cerebral blood flow in order to obtain optimum brain temperature. Some of the conditions which will! determine the efficiency of the venous temperature control system are: (ll) environmental temperature, (2.) environmental humidity, and (3) nasal respiratory rate and amplitude, and (4) emotional stress.

If the ambient temperature is excessively high, heat transfer from the nasal vessels to the inhaled ambient air is reduced and cardio-arterial adjustments occur (i.e., an increase in heart rate (HR), an increase in systemic arterial pressure (ABP), and an increase in cerebrospinal fluid pressure (CSFP)), which are evidence of an increase in cerebral blood flow. The opposite cardio-arterial adjustments occur when the temperature is excessively low. in further explanation, the venous temperature control system, by itself, is able to regulate brain temperature as long as ambient temperature remains within as yet undetermined limits of heat and cold. Consequently, it is only when these limits of heat and cold are exceeded that the cardio-arterial control system comes into play by adjusting cerebral blood flow in an effort to complement the venous temperature control system. The role of the cardio-arterial control system, when the heat and cold temperature limits are exceeded, is that of obtaining optimum brain temperature regulation. These relationships have been verified by experimental work conducted in our laboratory. Using running water to obtain maximum heat transfer both toward the blood in the nasal vessels (with 42-50 C water irrigation) and away from the blood in the nasal vessels (with C water irrigation), we were able to obtain the cardio-arterial adjustments to be described below in connection with FIG. 3.

Humidity is another factor influencing the amount of heat transfer occurring in the venous temperature control system. In this regard, humidity affects the amount of cooling which occurs on the mucosal surface. For instance, the higher the humidity, the less the heat loss occurring from the mucosal surface as a result of evaporation. For this reason, the limits of ambient heat and cold, beyond which the cardio-arterial control system comes into play to complement the venous temperature control system, are partially determined by humidity. We believe that, under normal conditions, the resultant loss os efficiency in heat transfer in the venous temperature control system due to humidity would be compensated for by the cardio-arterial adjustments pointing toward increasing blood flow as previously described.

The temperature of the blood in the venous temperature control system can be lowered by increasing the nasal respiratory rate and amplitude in man. Also, the CSFP (a part of the cardio-arterial control system) can be lowered to zero in man by increasing respiratory rate and amplitude under conditions which make it unlikely that blood gas levels would completely account for the reduction. Although different procedures were used, similar results to those in man, i.e., lowered blood temperature in the venous temperature control system during respiration and vice versa and lowered CSFP during deep respirations, were obtained in our laboratory using the dog. In man the temperature was lowered by increasing the respiratory rate and amplitude, whereas in the dog it was lowered by irrigation of the nasal mucosa with 15 C tap water. In both species it appears that the cold temperature limit for regulation of brain temperature by the venous temperature control system had been exceeded thereby activating the 'cardio-arterial control system. Also, in both species some degree of feedback control of the two systems was removed in man by voluntary respirations and in the dog by irrigation under anesthesia. this assumption was supported by the fact that the changes in CSFP seen in both species were due to over-cooling of the venous blood in the-venous temperature control system.

The interaction between the venous temperature control system and the cardio-arterial control system to obtain optimum brain temperature can be manipulated and changed in useful ways. First, as a method for inducing differential brain hypothermia, the temperature of the blood in the venous temperature control system can be lowered to a level at which not even the cardioarterial control system can adequately compensate,

and brain temperature is thereby lowered. Among the Additionally, these two control systems can be manipulated so as to reduce cerebral blood flow (along with a decrease in ABP, CSFP, and HR) as noted during the cooling of the venous blood destined for the cavernous sinus. This would: (a) facilitate hemostasis during brain surgery and (b) facilitate surgical procedures by reducing brain volume and intercranial pressure.

It appears that stimulating the cardio-arterial control system with temperature invokes a unique autonomic response in the circulatory system, i.e., increase in ABP (vasoconstriction) and an increase in CSFP (vasodilatation) with heat, and the opposite ABP and CSFP responses with cold. This autonomic response to temperature is unique in that it is not the all-or-nothing response usually seen with autonomic stimulation, i.e., increase in AB? (vasoconstriction) and a decrease in CSFP (vasoconstriction) with epinephrine; and the opposite ABP and CSFP responses with artificial stimulation of the vagus.

In this regard, it is recognized that alpha and beta adrenergic receptors make it possible for the adrenergic nerves to dilate blood vessels as well as to constrict them. However, this dual response has not be demonstrated for the cholinergic nerves to our knowledge, consequently vasoconstriction would have to be the result of adrenergic nerve stimulation. In view of this, the constriction of cerebral vessels during cold water irrigation of the nasal mucosa (if due to autonomic stimulation) would have to be due to adrenergic action. There is definite evidence, on the other hand, that the adrenergic nerves are not responsible for the extracranial vasodilatation during cold water irrigation (decrease in ABP). That is, in our laboratory cold water irrigation was accompanied by excessive lacrimation which is considered to be a response to cholinergic stimulation.

The all-or-nothing response of the blood vessels to stimulation of the autonomic nervous system for epinephrine (constriction) and electrical stimulation of the vagus (dilatation) appears to be for the purpose of maintaining a constant cerebral blood flow. The response of the autonomics to the stimulus of temperature applied to the cardio-arterial control system, on the other hand, appears to be for the purpose of varying blood flow (increase in ABP, HR and CSFP from heat indicating an increase in flow; decrease in ABP, HR and CSFP from cold indicating a decrease in flow).

Turning now to FIG. 1, the nature of our experiments will be described. The subject is a dog, only the head of which is illustrated. Resting before the nose of the dog is a base plate generally designated by reference numeral 10 in which there are embedded an input lead 11 and a bifurcated output conduit 12 leading into the nose of the dog as illustrated. The input conduit 11 is connected to a source of cool water (not shown) or other cooled fluid such as air, and the distal ends of the bifurcated output conduit 12,12 are located adjacent the tip of the dogs nose and oriented so as to direct a stream of the cool water principally onto the alar folds of the dogs nose. The pressure of the water passingthrough the output conduits 12,12 is only sufficient to cause an upward flow of water of only a few inches.

Leading from the alar folds of the dog are two angularis oculi veins, a left and a right vein, which communicates venous blood from the alar folds into the cavernous sinus of the dog. Placed adjacent the left and right angularis oculi veinsare first and second thermistors designated respectively 13 and 14, and these are arranged by means of wires l6-and 17 respectively to monitor the temperature of the blood flowing inthe left and right angularis oculi veins of the dog.

EXPERIMENTS Eight dogs weighing from 3040 pounds were anesthetized and placed in ventral recumbancy (as illustrated) .with the head elevated by securing thezygomatic arches to a metal rack with bone screws. The long axis of the head was held at a 45 angle in relation to the long axis of the neck by ventral traction on the anterior extremity of the upper jaw.

1 Five dogs (Exps. 8, 9, 10, ll, 12) were anesthetized with 20 percent Urethan (ethyl carbamate manufactured by Matheson, Coleman and Bell of East Rutherford, New Jersey) in distilled water given intravenously to effect. Three dogs (Exps. 13,14, 15) were first given Surital (sodium thiamylal manufactured by Parke, Davis & Co. of Detroit, Mich.) 4 percent intravenously. Anesthesia was then continued with Metofane (methoxyflurane manufactured by Pitman-Moore of Indianapolis, Indiana) in a Heidbrink Model 2000 closed circle anesthetic gas machine Endotracheal catheters were employed in all experiments.

Respiration was monitored only in experiments 8 through 12 by a thermistor needle probe placed in the endotracheal catheter. Body temperature was monitored via a rectal probe and a Telo-Thermometer. The temperature of the right and left angularis oculi veins were monitored by needle thermistors placed on the deep face of the veins near the medial canthus of the eye as shown at 13 and 14 of FIG. 1. The temperature of the water irrigating the end of the nose was monitored by a thermistor placed in the water hoselO at about four in. from the open ends of the irrigating tube 12,12 which, in turn, were placed in the nostrils as illus trated. The systemic arterial pressure was measured by connecting a fluid-filled cannula from the femoral artery to a Statham P23BC pressure transducer. The cerebrospinal fluid pressure was measured through a 19- gauge needle inserted into the cisterna magna and attached by a fluid-filled cannula to a Statham P23BC pressure transducer. The EKG was also sensed and processed by a Grass Model 7P4AB Tachograph for heart rate indication. All of the transduced parameters along with a marking signal were recorded on a -channel GrassModel 7 ink-writing recorder. The two pressure signals and the heart rate signal were electrically damped to provide a write-out of mean values.

The experimental procedure carried out with each animal was as follows. After anesthesia and attachment to the rack, a lO-l5 minute rest period was allowed in order to establish resting or normal values of all recorded parameters. Then the tip of the nose (with special emphasis upon the alar fold of the maxilloturbinate) was irrigated with cold water C.) for 10-15 minutes. The experimental trials then followed. A trial is defined as one change in irrigating water temperature (from cold to hot or from hot to cold). The hot water temperature was in the range of 45-48 C.

After completion of the trials the brains were probed. The probe on the right side was inserted after a maximum increase in both cerebrospinal fluid pressure and systemic pressure had been obtained during hot water irrigation. The probe on the left side was inserted after the right side probe had been withdrawn ,and after a maximum decrease in both pressures had been obtained during cold water irrigation.

A 4-inch long 25-gauge needle was employed as the brain probe. It was passed through holes 2 mm in diameter drilled through the skull with a dental burr just posterior to the frontopariental suture and l cm lateral to the dorsal midline on both the right and left sides. The probe was passed ventrally through the dura mater and brain until it impinged on the bone at the base of the skull and then withdrawn a measured distance.

When the physiological aspects of the experiments were completed, the brains were removed from six dogs Three dogs (Exps. 10, 11 12) were removed from the rack, placed in lateral recumbancy, exsanguinated, and embalmed with 10 percent formalin solution through the common carotid artery. The probe tracts in the brains were then exposed and photographed. Three dogs (Exps. 13, l4, 15) were exsanguinated while still in the rack and comparisons of the two sides of the unembalmed brainwere made by visual inspection and then photographed.

In all of the 56 reported trials during which the temperature of the irrigating water was increased or decreased, the cerebrospinal fluid pressure (CSFP) and femoral arterial blood pressure (ABP) always increased or decreased respectively. In the fifty trials in which heart (HR) was monitored, this parameter, with a few exceptions, also showed an increase or decrease with a respective increase or decrease in irrigating water temperature. The above responses when applied to two succeeding trials (cold to hot and back to cold) are defined by the authors to be examples of overall normal responses. Furthermore, the temperature of the angularis oculi vein always followed in the same direction as the water temperature.

The significant results are summarized in Table I. The table indicates that there were: 32 trials carried out under Urethan-chlorolose anesthesia and 24 with Metofan anesthesia. Also, there were 28 Metofane and 28 hot-to-cold trials. The pressure and time entries in the table are the means values obtained in each type of trial.

FIG. 2 graphically illustrates the pressure and time relationships recorded in Table I. In FIG. 2, the abscissa is time; and the ordinate is pressure. The results of hot and cold water irrigation are shown above and below the abscissa respectively. The solid lines represent changes in cerebrospinal fluid pressure, and the dashed lines represent changes in femoral arterial blood pressure. Time was measured as starting when the water temperature change was detected by the thermistor in the water-conducting tube. The beginning point of each line, which lies on the time axis, is the mean time for the first detectable pressure change to occur. The vertical coordinate of the end point of each line is the mean maximum change in pressure that occurred. Finally, the horizontal coordinate of the end point of each line is the mean time it took for the maximum pressure change to appear.

FIG. 2 illustrates the following points:

Whether the irrigating water temperature was hot or cold:

1. All pressure levels reached their maximum excursions sooner under Urethan-chlorolose anesthesia.

2. The rate of change of pressure (slope of each line) was greater in absolute value with Urethan anesthesia.

3. In 3 of the 4 pairs of lines (paired by type of pres sure), the initial change in pressure came sooner when Urethan-chlorolose anesthesia'was used.

4. Greater pressure changes were noted with Metofane anesthesia.

Regardless of the type of anesthesia used:

1. All pressure levels reached their maximum excursion sooner under hot water irrigation (change from cold to hot).

2. Hot water irrigation caused greater pressure changes to occur in all cases except in the ABP measurement under Metofane anesthesia.

3. The rate of change of each pressure was greater in absolute value with hot water irrigation.

In our experiments the responses of the cardioarterial system to temperature changes in the brain were such that the pressure and resistance relationships seen in the classical response to autonomic stimulation did not apply. That is, a decrease in both cerebrospinal fluid pressure (CSFP) and heart rate (HR) and an increase in femoral arterial blood pressure (ABP) usually seen during sympathetic stimulation; and an increase in CSFP and HR along with a decrease of ABP usually seen invagal stimulation did not usually occur. Vasoconstriction (sympathetic), vasodilatation (vagus) and changes in heart rate are manifestations, both intracranially and extracranially, of autonomic stimulation. These responses are (among other possibilities) aimed at maintaining a more or less constant cerebral blood flow. The nature of the responses of the arterial system to temperature changes in our experiments, however, are interpreted to have changed cerebral blood flow. As cerebral resistance increased (vasoconstriction decrease in CSFP), ABP did not increase, but instead it decreased. Inasmuch as heart rate (HR) also decreased, indications are that the flow of blood to the brain diminished when the alar fold of the maxilloturbinate'was cooled. Further, when the temperature of the alar fold was increased by irrigation with warm water CSFP, ABP and HR increased, indicating an increased flow of blood to the brain. We therefore conclude that by cooling the nasal mucosa to a degree such that neither the venous temperature control system nor the cardio-arterial control system was able to compensate, the temperature of the brain was lowered. The lowering of the brain temperature was accompanied by cardioarterial changes which indicated that blood flow to the brain was being reduced.

It appears that there are two routes over which the brain receives information relating to temperature changes originating at the nose. In one of the above cited reports, we noted that when the irrigating water was changed from hot to cold, the temperature response in the region of the posterior communicating artery lagged the response of the angularis oculi vein by 6 seconds. In the present series of experiments, changes in CSFP (FIG. 3C), ABP (FIG. 3B), and HR (FIG. 3A) always lagged the temperature changes in the irrigating water (FIG. 3E) and usually lagged temperature changes in the angularis oculi veins (FIG. 3F). FIG. 3D

is a common time marker for all the graphs of FIGS. 3A-3C, and 3E-3G. In one experiment, however, pressure and rate changes occurred before temperature changes were observed in the angularis oculi veins.

There is a possibility in view of this that in some cases the brain is receiving stimuli by a route other than the venous return route from the nose to the cavernous sinus. The time lag between the change in water temperature and the changes in pressures and heart rate (3-5 seconds), considering that water temperature was being measured in the conducting hose 4 inches before reaching the nose, suggests that the second route is a nerve pathway.

Body temperature varied slightly with the temperature of the irrigating water (see FIG. 3G). Increases in body temperature were presumed to be the result of warming the circulating blood by the hot water which was irrigating the end of the nose and vice-versa.

The swelling, produced by passing a probe into the brain during hot water irrigation, was found to be irreversible even after a cold water irrigation span of 10 minutes. This response appeared to be unilaterally confined to the side where the injury occurred. A rapid increase in CSFP, in addition to the increase obtained during hot water irrigation, was often seen shortly after the probe was inserted. In one such experiment the CSFP began to increase 24 seconds after insertion of the needle and during the ensuing seconds the pressure increased by 4mm/Hg. Since the CSFP was monitored in the cysterma magna, it is assumed that the same CSFP was exerted equally on both cerebral hemispheres. It thus appears that the swelling seen on the right side could not have been caused by interference with venous drainage from the cerebral cortex to the dural sinuses. That is, if drainage interference had been the cause both hemispheres would have been swollen. As it was, the left hemisphere actually appeared to be shrunken. The response of the brain to injury, i.e., an increase in blood flow to the injured area, appears to be similar to the inflammatory response to injury seen in other parts of the body.

Some conception of the effect of temperature on the dynamics of the cerebral vasculature may be had when considering that CSFP was reduced from +7 to 2 mm/I-Ig in approximately 1 minute in the face of a presumed persistent swollen condition in the right cerebral cortex. However, in other trials where the probe was withdrawn, with continued hot water irrigation, the CSFP remained on the positive side.

The side of the brain probed during cold water irrigation was more firm than the side probed during hot water irrigation. This was more evident in the fresh specimens than in those that were embalmed for probe tract studies. In fact, obtaining a cross section for photography was difficult in the fresh specimens because the right side (probed during hot water irrigation) was very flacid. The left side (probed during cold water irrigation) was firm, held its shape well and sliced much the same as liver. The results obtained, relative to inflammation and swelling, by irrigating the alar fod with cold tap water are in agreement, thus far, with those of other researchers obtained by immersion of the animals in ice water.

An investigation of the relative amounts of hemmorrhage in the probe tracts made during hot and cold water irrigation revealed hemorrhage to be more extensive when hot water was being used. The tract made during cold water irrigation was evidenced by a very faint gray line dorsal to the lateral ventricles.

We have concluded that there are two physiological mechanisms which are responsive to hot and cold water irrigation of the alar fold of the maxilloturbinate; namely, the venous temperature control system and cardio-arterial control system both of which have already been discussed. Three physiological variables which appear to be aumanifestation of these mechanisms are systemic blood pressure (as measured in the femoral artery), cerebrospinal fluid pressure (which reflects cerebral vasodilatation or vasoconstriction) and heart rate. We have observed that these variables normally respond in such a way that they appear to vary cerebral blood flow.

a. The response of the cerebral vasculature to hot water irrigation is vasodilatation (increase in cerebrospinalfluid pressure) which is usually accompanied by a concurrent increase in femoral arterial blood pressure and heart rate.

b. The response of the cerebral vasculature to cold water irrigation is vasoconstriction (decrease in cerebrospinal fluid pressure) which is always accompanied by a concurrent decrease in femoral arterial blood pressure and usually in a decrease in heart rate.

In general, the animals had a greater sensitivity to changes in water temperature when anesthetized with urethan than with metofame. However, greater pressure changes were observed when metofame was used.

Swelling occurred when the brain was probed during continued hot water irrigation while swelling did not occur when the brain was probed during continued cold water irrigation.

Turning now to FIG. 4, there is a block-schematic diagram shown of a system intended for use in inducing brain hypothermia and changing the flow of blood to the brain in humans. Reference numeral generally designates a Wheatstone bridge circuit arrangement having three precision resistors 21, 22 and 24 in adjacent branches and one sensing thermistor 23 in the other branch of the bridge. The thermistor 23 is intended for surface placement on the skin of the patient over the left or right angularis oculi vein. There may be included a separate system for measuring temperature 'in the other of these veins, of course. The thermistor should be suitably embedded in heat insulating material so that only the surface which engages the skin of the patient is exposed and sensitive to temperature changes. The bridge 20 is energized by means of a battery 25 and the output signal from the bridge, representative of changes in the temperature of the angularis oculi vein of the patient is taken from diagonally opposite corners of the bridge and fed to a differential amplifier 26.

The other input to the amplifier 26 is received from a circuit including a variable resistor 27 and a reference voltage source, schematically denoted by +V The signal thus generated and fed into the reference input of amplifier 26 is a reference signal against which the signal from the bridge circuit 20 is compared. The output signal of the amplifier 26 is an error signal representative of the difference between the temperature of the venous blood in the angularis oculi vein and a signal representative of reference temperature.

Any suitable means may be employed for holding the thermistors 23 and 24 in contact with the surface of the skin over the angularis oculi veins, but care should be taken so that the thermistors are sensitive only to the temperature of those veins and do not impede blood flow in the veins.

The amplifier 26 is energized by means of a power supply 28, and the output signal of the amplifier 26 is fed to a meter 29 which may simply be a voltage meter calibrated to display the error in temperature. The output signal of the amplifier 26 is also fed through a power amplifier 30, the output of which is connected to a set of normally open contacts of a relay 31. Power amplifier 30 is a conventional linear amplifier designed to boost power level sufficient to drivea servo-motor 32 when the coil of relay 31 .is energized to close its contacts. A square wave oscillator 33 is powered by the power supply 28 and has its output connected to the coil of relay 31 for energizing that relay periodically.

The oscillator 33 may be of conventional design, and

it preferably has a variable frequency rate and a variable duty cycle. The function of the oscillator 33 is to provide timing means to delay operation of the error signal from amplifier 26 for a period of time at least sufficient to permit the system to sense temperature changes in the angularis oculi veins produced by irrigating the nasal mucosa. That is, it takes a few seconds from the time at which irrigation 'of the nasal mucosa begins until a corresponding temperature change is sensed in the angularis oculi vein. The oscillator 33, then, periodically interrupts the transmission of the error signal representative of temperature of the blood in the angularis oculi vein for a predetermined time, sufficient to enable a quiescent state to be reached after the application of a coolent. By having the oscillator 33 of variable frequency, the periodicity of this time delay may be controlled; and by having the duty cycle of the output square wave of the oscillator 33 also being variable, it is possible to control the time delay effected by it. in a typical situation, the duty cycle may be such that the oscillator 33 would energize the relay 31 for a time of 20 to 40 per cent of its cycle which may nominally be around 10 seconds, but variable, as mentioned.

When relay 31 is energized andits contacts closed, the output of power amplifier 30 drives the servomotor 32 which also receives power from the power supply 28 as indicated.

The shaft of the servomotor 32 (as diagrammatically indicated by the dashed line 32A) controls a flow valve 34 which passes a fluid such as compressed gas from a source 35. The gas from the source 35 passes through a pressure regulator 36 into the flow valve 34 and thence into a heat extractor or cooler 37. The cooler 37 extracts heat from the gas passing through it and it may take the form of stainless steel tubing immersed. in ice water. The function of the cooler 37 is to maintain a constant but adjustable temperature. The cooling ability of the gas, of course, increases with the flow rate of the gas which is predetermined by the adjustment of the flow valve 34 via servomotor 32. The gas emanating from the cooler 37 is treated by means of a humidifier and source of anesthetic 39. The gas is humidified so that the nasal membranes upon which the gas impinges will remain moist. if desired, graded amounts of local anesthesia may be applied to the nasal membranes to insure adequate venous drainage.

Having thus described indetail a method and apparatus for practicing our invention, persons skilled in the art will be able to modify certain of the steps disclosed and to substitute equivalent elements for those which have been described while continuing to practice the inventive principles; and it is, therefore, intended that all such modifications and substitutions be covered as they are embraced within the spirit and scope of the appended claims.

We claim:

1. A system for controlling the temperature of the brain of an animal comprising temperature sensitive means sensing the temperature of blood the angularis oculi vein of said animal for generating a signal representative of said temperature; circuit means receiving said signal for generating a signal representative of a difference between the temperature in said angularis oculi vein and a reference temperature; a source of fluid; means for controlling the flow rate of said fluid responsive to said error signal; timing circuit means for inhibiting said control for a predetermined time sufficient for a change in said flow rate to be sensed by said temperature sensitive means; and means for directing said cooled gas against the nasal mucosa of said animal.

2. The apparatus of claim 1 wherein said fluid is a gas and further comprising means for humidifying said fluid gas.

3. The system of claim 1 further comprising means for introducing a local anesthetic into said fluid stream to apply said anesthetic to said nasal mucosa.

4. Apparatus for controlling the brain temperature of an animal comprising: temperature sensitive means adapted for placement in close proximity to the angularis occuli vein of the animal for generating a signal representative of the temperature of the venous blood in said vein flowing from the nasal mucosa; means including a source of fluid cooled below the normal temperature of said venous blood and adapted to direct said fluid against the nasal mucosa of the animal, said means further including control means for controlling the flow rate of said fluid; circuit means receiving said temperature signal for driving said control means to vary the flow rate of said fluid to efiect a desired temperature in said venous blood, said circuit further including means for delaying the driving of said control means in response to a sensed temperature for a period of time between the application of said fluid and sensing of the corresponding change in temperature sensed by said temperature sensitive means.

5. The apparatus of claim 4 wherein said fluid is a gas and further comprising means for adding an anesthetic to said gas prior to contacting said nasal mucosa; and means for adding humidity to said gas after cooling the same and prior to contacting said nasal mucosa. 

1. A system for controlling the temperature of the brain of an animal comprising temperature sensitive means sensing the temperature of blood the angularis oculi vein of said animal for generating a signal representative of said temperature; circuit means receiving said signal for generating a signal representative of a difference between the temperature in said angularis oculi vein and a reference temperature; a source of fluid; means for controlling the flow rate of said fluid responsive to said error signal; timing circuit means for inhibiting said control for a predetermined time sufficient for a change in said flow rate to be sensed by said temperature sensitive means; and means for directing said cooled gas against the nasal mucosa of said animal.
 2. The apparatus of claim 1 wherein said fluid is a gas and further comprising means for humidifying said fluid gas.
 3. The system of claim 1 further comprising means for introducing a local anesthetic into said fluid stream to apply said anesthetic to said nasal mucosa.
 4. Apparatus for controlling the brain temperature of an animal comprising: temperature sensitive means adapted for placement in close proximity to the angularis occuli vein of the animal for generating a signal representative of the temperature of the venous blood in said vein flowing from the nasal mucosa; means including a source of fluid cooled below the normal temperature of said venous blood and adapted to direct said fluid against the nasal mucosa of the animal, said means further including control means for controlling the flow rate of said fluid; circuit means receiving said temperature signal for driving said control means to vary the flow rate of said fluid to effect a desired temperature in said venous blood, said circuit further including means for delaying the driving of said control means in response to a sensed temperature for a period of time between the application of said fluid and sensing of the correspoNding change in temperature sensed by said temperature sensitive means.
 5. The apparatus of claim 4 wherein said fluid is a gas and further comprising means for adding an anesthetic to said gas prior to contacting said nasal mucosa; and means for adding humidity to said gas after cooling the same and prior to contacting said nasal mucosa. 